Project Summary/Abstract Traumatic peripheral nerve injuries incapacitate hundreds of thousands of people in the United States and worldwide each year. Despite the regenerative ability of the peripheral nerves, full recovery is rare. Therapeutic exercise in the form of treadmill training is a non-invasive technique that has been shown to encourage recovery by enhancing axon regeneration and promoting the restoration of synaptic inputs onto motoneurons. This enhancement is sex-dependent with males and females requiring different exercise patterns to promote regeneration. The mechanisms underlying this sex difference are unclear but likely involve sex steroid hormones. Estrogen has been shown to play a role in motor neuron regeneration. The overall goal of this proposal is to study the estrogen dependence of the effects of treadmill exercise on neuronal participation in regeneration and synaptic reorganization after peripheral nerve injury. In Aim 1, the effects of estrogen receptor signaling on motor and sensory axon regeneration will be studied by blocking estrogen receptors during treadmill exercise. The number of motoneurons and dorsal root ganglion neurons whose axons regenerate successfully will be quantified. In Aim 2, we will assess the requirement for estrogen signaling in the exercise-mediated restoration of inputs onto motoneurons after peripheral nerve injury. Estrogen receptors will be blocked during exercise, and synaptic reorganization will be characterized and quantified. Estrogen therapy is already in use clinically. The results of these experiments will allow us to further develop estrogen therapy as a pharmacological treatment for patients suffering from traumatic peripheral nerve injuries, especially when participating in treadmill exercise is not possible.